海马GC关键功能基因甲基化调控在联结选择性剖宫产与子代神经精神发育异常中的作用

Since the elective caesarean section (ECS) rate is dramatically increasing worldwide, the negative effect of ECS on infant neuropsychological development has aroused much controversies. The surges of glucocorticoid (GC) release stimulated by natural delivery is necessary for infant neuropsychological development. Infants born via ECS, however, typically lack the necessary release of stress hormone. Thus, this study hypothesizes that "methylation of GC key funtional genes in hippocampus may be altered by low level of delivery stress, which bridges ECS and infant abnormal neuropsychological development". A population-based birth cohort will be set up to observe the differences in neuropsychological development in infants born via ECS and vaginal delivery and examine the relationship between neuropsychological development and cortisol levels immediately, 3 months, 6 months after birth. Taken together, ECS animal model will be established to determine the expression and methylation of Fkbp5 and Nr3c1 genes in both hippocampus and blood in mice with vaginal delivery and ECS at different postnatal time points, and to examine the relationship of methylation of target genes between blood and hippocampus, as well as its association with learning and memory functions. And then, findings of animal study will be confirmed in human samples. This study will offer the very direct evidence for the relationship between ECS and infant neuropsychological development and preliminarily elucidate the underlying molecular mechanisms. Meanwhile, the present research will also explore the possibility that methylation states of target genes in blood might be acted as the biomarkers of the same genes in brain. It is expected to provide not only the ideas of epegenetic research on human brain, but also new evidence-based conclusions helpful in controlling the rising ECS rates.

无指征选择性剖宫产（ECS）率的急剧上升引发了学者对ECS致子代神经精神发育不良效应的热烈争议。自然分娩应激引起的糖皮质激素（GC）正常升高有利于子代神经精神发育，而ECS取消了自然分娩GC的正常上升过程，因此我们假设"低水平分娩应激影响海马GC关键功能基因的甲基化调控，进而联结了ECS与子代神经精神发育异常"。本研究建立人群出生队列，观察自然分娩和ECS婴幼儿神经精神发育状况及其与脐带血GC和出生后3个月、6个月时唾液GC的相关性；用ECS小鼠模型，分析两种分娩方式的仔鼠不同时点海马及外周血GC关键功能基因Fkbp5和Nr3c1甲基化程度及mRNA、蛋白表达水平，分析海马和外周血目标基因甲基化的关系及其与学习记忆能力的关联，再经队列样本分析印证。研究将为ECS影响子代神经精神发育提供直接证据，并初步阐明其分子机制，可望为人脑功能的表观遗传研究提供思路，也为控制高ECS率提供循证依据。

随着全球范围无医学指征的选择性剖宫产（ECS）比例不断增加，剖宫产对母婴健康的影响引起了广泛关注，特别是对儿童神经精神发育的影响。ECS取消了自然分娩时糖皮质激素（GC）的正常上升过程，这种“低应激”形式对子代神经精神发育影响的机制研究较少。.本研究建立前瞻性出生队列，系统收集妊娠各期、分娩期和儿童期相关信息和生物学样本。结果发现，研究地区总剖宫产率为50.5%，无指征ECS率为26.2%。孕中期高水平妊娠特有焦虑是初产妇ECS的独立预测因素，无指征ECS与高水平胎盘氧化应激和炎症应激反应有关。就儿童发育而言，与自然分娩的儿童相比，ECS儿童在生命早期具有明显的加速生长现象，表现为3、6、9和18个月年龄别身高和年龄别体重显著增高。ECS与6月龄婴儿粗大动作发育迟缓有关。脐血皮质醇水平在无指征ECS组最低；作为调节糖皮质激素受体（GR）敏感性的关键基因，脐血FK506结合蛋白5基因（FKBP5）mRNA表达水平增高可能与GR抵抗有关。同时，课题建立的剖宫产动物模型（ICR小鼠）显示，与自然分娩的仔鼠相比，剖宫产仔鼠存在学习和记忆能力损伤。剖宫产仔鼠海马糖皮质激素受体基因（Nr3c1）和Fkbp5 mRNA和蛋白表达水平在产后不同时点均显著增高；产后14天，剖宫产仔鼠海马Nr3c1 exon 17和Fkbp5 intron5甲基化水平均显著降低。另外，拓展研究显示，ECS增加学龄前儿童超重、肥胖和哮喘的发生风险；妊娠39周前无医学指征ECS儿童在学龄前期将面临更多的情绪和行为问题。.研究通过人群-动物-人群的循证，提示ECS对子代神经精神发育存在一定程度的损伤，验证了“低水平分娩应激影响海马GC关键功能基因的甲基化，进而联结了ECS与子代神经精神发育异常”这一假说。研究通过大样本出生队列，为ECS对子代身心发育影响提供了直接证据，并初步验证了表观遗传调控的作用，具有一定的理论意义。同时，研究也搭建起分子生物学、围生医学和预防医学之间的桥梁，为控制我国高ECS率提供循证依据，并将进一步助力发育源性疾病的早期精准预防。

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